Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC

The enzyme LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is broadly conserved across Gram-negative bacteria and is essential for synthesis of lipid A, the membrane anchor of the lipopolysaccharides (LPSs), which are a major component of the outer membrane in nearly all Gram-negative bacteria. LpxC has been the focus of target-directed antibiotic discovery projects in numerous pharmaceutical and academic groups for more than 20 years. Despite intense effort, no LpxC inhibitor has been approved for therapeutic use, and only one has yet reached human studies. This article will summarize the history of LpxC as a drug target and the parallel history of research on LpxC biology. Both academic and industrial researchers have used LpxC inhibitors as tool compounds, leading to increased understanding of the differing mechanisms for regulation of LPS synthesis in Escherichia coli and Pseudomonas aeruginosa.